Immunology · Year 2 · from Immunology
Case 3: Chronic Antibody-Mediated Rejection
Patient Demographics
- Age: 48 years old
- Sex: Female
- Ethnicity: Hispanic
Chief Complaint
Gradually rising creatinine over 2 years, now with heavy proteinuria
History of Present Illness
A 48-year-old woman with a kidney transplant from 8 years ago presents for evaluation of progressively worsening graft function. Her creatinine has slowly risen from a baseline of 1.3 mg/dL to 2.5 mg/dL over the past 2 years. Recent urinalysis shows 3+ protein. She reports compliance with her immunosuppressive medications and denies any acute symptoms. She admits to occasionally missing her evening mycophenolate dose.
Transplant History
- Original disease: Polycystic kidney disease
- Transplant: Living unrelated donor (spouse), 8 years ago
- HLA matching: 3/6 mismatch
- Initial course: Excellent function (creatinine 1.0-1.3 mg/dL for first 6 years)
- Year 6: Episode of BK nephropathy, treated with immunosuppression reduction
- Maintenance: Tacrolimus 3mg BID, mycophenolate 500mg BID, prednisone 5mg daily
Laboratory Workup
| Test | Result | 2 Years Ago | Reference |
|---|---|---|---|
| Creatinine | 2.5 mg/dL | 1.4 mg/dL | 0.7-1.3 mg/dL |
| eGFR | 22 mL/min | 48 mL/min | >90 mL/min |
| Proteinuria | 2.8 g/24hr | 350 mg/24hr | <150 mg/24hr |
| Tacrolimus level | 5.8 ng/mL | -- | Target 5-8 ng/mL |
| DSA (HLA-DR) | MFI 12,500 | Negative | Negative |
| CMV, BK PCR | Negative | -- | Negative |
Kidney Biopsy Findings
- Light microscopy:
- Glomeruli: Double contours of GBM (transplant glomerulopathy)
- Interstitium: 40% interstitial fibrosis and tubular atrophy (IFTA)
- Vessels: Moderate intimal fibrosis
- Peritubular capillaries: Capillaritis (inflammation)
- Immunofluorescence: C4d positive in peritubular capillaries (diffuse, >50%)
- Electron microscopy: GBM duplication, subendothelial widening
Diagnosis
Chronic Active Antibody-Mediated Rejection with transplant glomerulopathy
Discussion
Chronic antibody-mediated rejection (AMR) is a leading cause of late graft loss:
Pathophysiology:
- Development of de novo donor-specific antibodies (DSA)
- DSA bind to donor HLA antigens on graft endothelium
- Complement activation (C4d deposition)
- Endothelial injury leads to chronic vascular and glomerular damage
- Results in transplant glomerulopathy and progressive fibrosis
Diagnostic criteria for chronic active AMR:
- Morphological evidence of chronic tissue injury:
- Transplant glomerulopathy (GBM double contours)
- Peritubular capillary basement membrane multilayering
- Evidence of current antibody-graft interaction:
- C4d deposition or microvascular inflammation
- Serological evidence:
- Donor-specific antibodies (DSA) present
Risk factors in this patient:
- HLA mismatch (3/6)
- Prior BK nephropathy (reduced immunosuppression)
- Possible non-adherence (missed doses)
- Living unrelated donor (chronic immune stimulation)
Transplant glomerulopathy:
- Pathognomonic of chronic AMR
- GBM duplication from recurrent endothelial injury and repair
- Associated with heavy proteinuria
- Poor prognosis once established
Treatment
- Limited options for chronic AMR - largely irreversible
- Optimize immunosuppression: Ensure adequate tacrolimus levels; improve adherence
- Consider:
- Plasma exchange + IVIG (limited efficacy in chronic AMR)
- Rituximab (B cell depletion)
- Bortezomib (plasma cell depletion) - limited evidence
- Supportive measures:
- ACE inhibitor/ARB for proteinuria
- Blood pressure control
- Cardiovascular risk management
- Prepare for graft failure:
- Dialysis planning
- Retransplantation evaluation
Prognosis: Poor; most grafts with chronic AMR progress to failure within 3-5 years. Prevention through adherence and DSA monitoring is key.
Prevention strategies:
- Medication adherence counseling
- Regular DSA monitoring (every 6-12 months)
- Prompt treatment of acute AMR episodes
- Avoid unnecessary immunosuppression reduction